We have studied the functional interaction of the breast cancer susceptibility gene-1 (BRCA1) and the estrogen receptor (ER-1) for the past 10 years. During these studies, we observed that BRCA1 strongly inhibits ER-1 activity in breast cancer cells and blocks estrogen (E2)-stimulated gene expression and cell proliferation. The BRCA1 repression of ER-1 activity is due to a physical interaction of the BRCA1 and ER- 1 proteins, which we mapped at high resolution. From these studies, we generated a 3D model of the BRCA1: ER-1 complex and performed virtual screening of a small molecule library to identify compounds that might act as BRCA1-mimetics to insert deeply into ER-1 at key contact points. Of 40 such compounds that we tested, 6 strongly inhibited ER-1 activity, including several that yielded 50% inhibition at concentrations of only 3-4 <M. Hypothesis. BRCA1 mediates a number of functions, including its role as a caretaker gene in preserving genomic integrity. However, this role for BRCA1 does not explain why mutation carriers exhibit an excess incidence of specific tumor types, particularly breast cancer. We hypothesize that while its caretaker function contributes to tumor suppression, BRCA1 suppression of breast cancer development requires its ability to inhibit ER-1 activity. Conversely, it will be possible to prevent breast cancer by restoring or enhancing this function, using small molecule compounds that mimic critical aspects of the BRCA1: ER-1 physical interaction. Objectives. To test this hypothesis, we will carry out four specific aims: 1) To study the mechanism of action of BRCA1-mimetic drugs in human breast cancer cells; 2) To generate large quantities of our current lead compounds and synthesize structural analogs of the lead compounds to produce more potent compounds; 3) To test the lead compound and best analog(s) for their ability to inhibit estrogen-stimulated human breast cancer tumor growth in vivo in a xenograft model; and 4) To test the ability of several compounds to prevent the early stages of mammary cancer development in several mouse transgenic models. Significance. Our ultimate goal is to develop novel drugs for breast cancer prevention and/or treatment. Importantly, the BRCA1-mimetic compounds interact with ER-1 in a manner that is distinct from that of the selective estrogen receptor modulators (SERMs), such as Tamoxifen and Raloxifene. Thus, they may be useful by themselves, in combination with existing agents, or in cases of hormone-resistant breast cancer. PUBLIC HEALTH RELEVANCE: BRCA1 (breast cancer 1, early onset) is a human gene that belongs to a class of genes known as tumor suppressors, which maintain genomic integrity to prevent uncontrolled proliferation. Inherited variations (mutations) in the BRCA1 gene have been implicated in several hereditary cancer types, including breast and ovarian cancers. The goal of this research is to develop small molecule drug-like compounds that mimic the ability of the BRCA1 protein to insert into the estrogen receptor protein and inhibit estrogen action. These BRCA1-mimetic compounds may be useful in the prevention and/or treatment of breast cancer.